The function of the lower urinary tract is to store and periodically release urine. This requires the orchestration of storage and micturition reflexes which involve a variety of afferent and efferent neural pathways, leading to modulation of central and peripheral neuroeffector mechanisms, and resultant coordinated regulation of sympathetic and parasympathetic components of the autonomic nervous system as well as somatic motor pathways. These proximally regulate the contractile state of bladder (detrusor) and urethral smooth muscle, and urethral sphincter striated muscle.
The presence of β adrenergic receptors (βAR) in detrusor smooth muscle of various species, including human, rat, guinea pig, rabbit, ferret, dog, cat, pig and non-human primate has been evaluated using radioligand binding and/or functional studies in vitro. The latter typically involve measurement of relaxation in strips of bladder tissue pre-contracted using muscarinic agonists, endothelin agonists or KCl. Both approaches are complicated by the species differences among β3AR which impact the potency and pharmacological specificity of putative agonists and antagonists used to characterize β3AR. Nevertheless, in aggregate such pharmacological studies indicate there are marked species differences in the receptor subtypes mediating relaxation of the isolated detrusor, where β1AR predominate in cats and guinea pig, β2AR predominate in rabbit, and β3AR contribute or predominate in dog, rat, ferret, pig, cynomolgus and human detrusors. Expression of βAR subtypes in the human and rat detrusor has been examined by a variety of techniques, and the presence of β3AR was confirmed using in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR). Real time quantitative PCR analyses of β1AR, β2AR and β3AR mRNAs in bladder tissue from patients undergoing radical cystectomy revealed a preponderance of β3AR mRNA (97% cf 1.5% for β1AR mRNA and 1.4% for β2AR mRNA). Moreover, β3AR mRNA expression was equivalent in control and obstructed human bladders, as was relaxation evoked by the human β3AR agonist L-755507 in vitro. These data suggest that bladder outlet obstruction does not result in downregulation of β3AR, or in alteration of β3AR-mediated detrusor relaxation. β3AR responsiveness also has been compared in bladder strips obtained during cystectomy or enterocystoplasty from patients judged to have normal bladder function, and from patients with detrusor hyporeflexia or hyperreflexia. No differences in the extent or potency of β3AR agonist mediated relaxation were observed, consistent with the concept that the β3AR activation is an effective way of relaxing the detrusor in normal and pathogenic states.
Urinary frequency, urinary urgency is a disorder characterized by frequent and generally inappropriate strong urges to urinate. From a pathophysiologic point of view, urinary frequency, urinary urgency is most often associated with detrusor instability (“overactive bladder”), which may be intrinsic or may occur secondary to neurological conditions such as stroke or spinal cord injury. Urinary frequency, urinary urgency affects approximately 16% of both men and women; particularly in women, urinary frequency, urinary urgency often is accompanied by urinary incontinence, which is defined as socially inappropriate, involuntary loss of urine. Urgency with or without incontinence has been shown to negatively impact both social and medical well-being, and represents a significant burden in terms of annual direct and indirect healthcare expenditures. Importantly, current medical therapy for urgency (with or without incontinence) is suboptimal, as many patients either do not demonstrate an adequate response to current treatments, and/or are unable to tolerate current treatments (for example, dry mouth associated with anticholinergic therapy). See Ouslander J G. Management of Overactive Bladder. N Engl J Med 2004; 350:786-99. Therefore, there is need for new, well-tolerated therapies that effectively treat urinary frequency, urinary urgency and incontinence, either as monotherapy or in combination with available therapies.
β3AR are the most prevalent βAR subtype expressed on human detrusor smooth muscle. See Takeda H, Yamazaki Y, Akahane M, Akahane S, Miyata H, Igawa Y, Nishizawa O. Characterization of β-Adrenoceptor Subtype in Bladder Smooth Muscle in Cynomolgus Monkey, Jap J. Pharmacol 2002; 88:108-13. Like other βAR subtypes (i.e., β1AR, β2AR), agonist-promoted stimulation of membrane-bound β3AR results in increased intracellular levels of cyclic adenosine monophosphate (cAMP) via activation of G proteins and adenylyl cyclase. In isolated human bladder smooth muscle, activation of β3AR using subtype-selective agonists results in smooth muscle relaxation. Anticholinergics, which are the current mainstay of treatment for urinary frequency, urinary urgency and incontinence, also cause smooth muscle relaxation via inhibition of acetylcholine-promoted smooth muscle contraction. Thus, it is reasonable to hypothesize that other agents that relax bladder smooth muscle, such as β3AR agonists, may be effective for treating urinary urgency.
β2AR are also expressed on human detrusor, and clenbuterol, a β2AR-selective agonist, has been approved for the treatment of urinary frequency, urinary urgency in Japan. However, β2AR agonists are associated with significant mechanism-based side effects such as tachycardia due to stimulation of cardiac β2AR. Thus, use of β3AR-selective agonists may offer a therapeutic advantage by promoting selective detrusor relaxation while minimizing significant mechanism-based side effects such as those associated with anticholinergics or β2AR agonists.
Functional evidence in support of an important role for the β3AR in urine storage emanates from studies in vivo. Following intravenous administration to rats, the rodent selective β3AR agonist CL316243 reduces bladder pressure and in cystomeric studies increases bladder capacity leading to prolongation of micturition interval without increasing residual urine volume. In experimental models in rats detrusor instability can be evoked by outlet obstruction, with consequent bladder hypertrophy and spontaneous bladder contractions. Bladder hyperreflexia can be evoked by intravesicular instillation of acetic acid, PGE2 or other stimuli which activate sensory afferent fibers with attendant reduced voiding interval and spontaneous bladder contractions during filling. Hyperreflexia may also be induced by cerebral infarction (middle cerebral artery occlusion), the effects of which are attributed to decreased inhibitory suprapontine control. In the hyperreflexia paradigms, CL316243 administered intravenously dose-dependently normalizes voiding interval and produces decreases in voiding amplitude and increases in bladder capacity and compliance. In the detrusor instability paradigm CL316243 administered orally results in dose-dependent inhibition of spontaneous bladder contractions. See Takeda H, Yamazaki Y, Akahane M, Igawa Y, Ajisawa Y, Nishizawa O. Role of the β3-Adrenoceptor in Urine Storage in the Rat: Comparison Between the Selective β3-Adrenoceptor Agonist, CL316, 243, and Various Smooth Muscle Relaxants. J Pharm Exp Ther 2000; 293:939-45. See Woods M, Carson N, Norton N, Wesley S, Jeffery H, Argentieri T M. Efficacy of the [Beta]3-Adrenergic Receptor Agonist CL-316243 on Experimental Bladder Hyperreflexia and Detrusor Instability in the Rat. J Urol 2001, 166:1142-7. See Takeda H, Yamazaki Y, Igawa Y, Kaidoh K, Akahane S, Miyata H, Nishizawa O, Akahane M, Andersson K E. Effects of β3-Adrenoceptor Stimulation on Prostaglandin E2-Induced Bladder Hyperactivity and on the Cardiovascular System in Conscious Rats. Neurology and Urodynamics 2002; 21:558-65. Kaidoh K, Igawa Y, Takeda H, Yamazaki Y, Akahane S, Miyata H, Ajisawa Y, Nishizawa O, Andersson K E. Effects of Selective [beta]2 and [beta]3-Adrenoceptor Agonists on Detrusor Hyperreflexia in Conscious Cerebral Infarcted Rats. J Urol 2002; 168:1247-52.
Adequate sensory input is a prerequisite for normal bladder control and changes in sensory mechanisms may give rise to disturbances in bladder function. Thus, it has been proposed that urge incontinence is “a disease of bladder sensors”. See Klein, L. A.: Urge incontinence can be a disease of bladder sensors. J Urol., 139: 1010-10-14, 1998. In spinal health, afferent activity from the bladder is mediated largely by the myelinated Aδ-fibers that pass through the spinal tracts to the brainstem and then to the pontine micturition center. After spinal disruption, a different type of afferent pathway emerges that is mediated by unmyelinated C-fibers that are sensitive to capsaicin. It is thought that these primary afferent C-fibers drive the spinal segmental reflex pathway and may be involved in pathological conditions of the bladder including overactivity and incontinence.
A renewed interest in tachykinins (TK) and especially NK receptor antagonists, on the micturition reflex is due to the recent introduction of C-fiber neurotoxins (capsaicin and resinferatoxin) in urology for the treatment of both idiopathic micturition disorders and those related to neurological dysfunctions such as multiple sclerosis, Parkinson's disease and spinal cord injuries. See Maggi, C. A., Barbanti, G., Santicioli, P., Beneforti, P., Misuri, D., Meli, A. and Turini, D.: Cystometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex of humans. J. Urol., 142: 150, 1989. Lazzeri, M., Beneforti, P., Spinelli, M., Barbagli G., Turini D. Intravesical resiniferatoxin for the treatment of hypersensitive disorders: a randomized placebo controlled study. J Urol., 164:676-679, 2000. Dasgupta, P. and Fowler, C. J. Chilies from antiquity to urology. Brit. J. Urol., 80:845, 1997. Lecci A., birder, L., Meini, S., Giuliani, S., Tramontana, M., Criscuoli, M. Capsaicin and the micturition reflex: actions of tachykinins and other transmitters. Curr. Top. Pharmacol., 4; 193-220., 1998. M. B. Chancellor and W. C. de Groat, Intravesical capsaicin and resiniferatoxin therapy; spicing up the ways to treat the overactive bladder. J. Urol. 162; 3-11, 1999. Capsaicin, instilled directly into the bladder, was the first such agent used and it has been reported to achieve beneficial effects (i.e. increased bladder capacity) in ˜70% of patients. Resinferatoxin, which is ˜100-fold more potent than capsaicin, causes prolonged inactivation of C-fibers without the initial stimulatory effects. See Avelino, A., Cruz, F., Coimbra, A. Intravesical resinferatoxin desensitizes rat bladder sensory fibers without causing intense noxious excitation. A C-fos study. Eur J. Pharmacol., 378; 17-25, 1999. The introduction of these agents into humans was supported by several animal studies that showed local or systemic treatment with capsaicin or resiniferatoxin, at doses that depleted substance P and neurokinin A in the bladder, caused an increase in bladder capacity and reduced bladder hyperactivity. See Holzer-Petsche, U. and Lembeck, F. Systemic capsaicin treatment impairs the micturition reflex in the rat. Br. J. Pharmacol. 83; 935-941, 1984. Cheng, C. I., Ma, C. P. and de Groat, W. C. Effect of capsaicin on micturition and associated reflexes in rats. Amer. J. Physiol., part 2, 34; R132, 1993. Cheng, C. I., Ma, C. P. and de Groat, W. Effect of capsaicin on micturition and associated reflexes in chronic spinal rats. Brain Res., 678; 40-48, 1995. Maggi, C. A., Santicioli, P. and Meli, A.: The effects of topical capsaicin on rat urinary bladder motility in vivo. Eur. J. Pharmacol., 103; 41-51, 1984. Santicioli, P., Maggi, C. A. and Meli, A.: The effect capsaicin pretreatment on the cystometrograms of urethrane anesthetized rats. J. Urol., 133; 700-708, 1985. Thus, a possible role of tachykinins as sensory transmitters in the micturition reflex has been postulated and NK1 and/or NK2 receptor antagonists may induce the same effects as capsaicin by inhibiting the sensorial input from the bladder to the spinal cord, thus increasing the threshold to initiate micturition.
The effects of selective NK1 and NK2 receptor antagonists have been studied in various animal models of bladder function. Using a cyclophosphamide-induced model of bladder overactivity, it has been shown that two NK1 antagonists (GR 82334 and RP 67580) increased the volume threshold after i.t., but not i.v. administration. A moderate response in this model was also observed with the NK2 antagonist SR 48968 (10 nmol/rat), however the i.v. co-administration of NK1 and NK2, antagonists did not modify urodynamic variables in either vehicle- or cyclophosphamide-treated rats. See Lecci, A., Giuliani, S., Santicioli, P., Maggi, C. A. Involvement of spinal tachykinin NK1 and NK2 receptors in detrusor hyperreflexia during chemical cystitis in anaesthetized rats. Eur J. Pharmacol., 259; 129-135, 1994. Using RP 67580 and SR 48968, Ishizuka et al., found that spinal NK1 receptors are involved in the micturition reflex induced by bladder filling in animals with bladder hypertrophy secondary to outflow obstruction. See Ishizuka, O., Igwana, Y., Lecci, A., et al. 1994. Role of intrathecal tachykinin for micturition in unanesthetized rats with and without bladder outlet obstruction. Br. J. Pharmacol. 113, 111-123. Another study determined that intrathecal administration of GR 82334 blocked capsaicin-induced micturition reflex in rats. Importantly, at the same doses proved effective in the chemonociceptive reflex, GR 82334 did not affect the micturition reflex induced by bladder filling or the force of contraction induced by perineal pinching. See Lecci, A., Giuliani, S., Maggi, C. A. Effect of the NK-1 receptor antagonist GR 82334 on reflexly-induced bladder contractions. Life Sciences, 51; 277-280, 1992.
Scientists at Takeda Laboratories have investigated the effects of TAK-637 on lower urinary tract function in guinea pigs and cats. Kamo and Doi, reported that in decerebrate cats, TAK-637 (0.1, 0.3, 1 and 3 mg/kg i.v.) produced a dose-dependent increase in bladder capacity (maximal increase was 94%) without any significant reduction in voiding efficiency. TAK-637 at 3 mg/kg i.v. did not inhibit the micturition reflex induced by electrical stimulation of the rostral brainstem near the locus coeruleus, indicating that it does not impair the efferent pathways of the micturition reflex. These results suggest that TAK-637 increases bladder storage capability without inhibiting the voiding function of the lower urinary tract, presumably by inhibiting the afferent pathway of the micturition reflex rather than the efferent pathway. The systemic administration of TAK-637 decreased the number but not the amplitude of distension-induced rhythmic bladder contractions in guinea pig, an effect which was also observed in animals with severed spinal cords. TAK-637 also inhibited the micturition reflex induced by topical application of capsaicin (which stimulates primary afferent nerve endings in the bladder wall) onto the surface of the bladder dome. These results suggest that TAK-637 inhibits sensory transmission from the bladder evoked by both physiological and nociceptive stimuli by blocking tachykinin NK1 receptors, almost certainly at the level of the spinal cord. Furthermore, TAK-637 inhibits the spinal vesico-vesical reflex induced by electrical stimulation of the proximal cut end of the pelvic nerve in spinal animals, but not bladder contractions induced by electrical stimulation of the distal cut end of the nerve. Tissue bath studies showed that TAK-637 had no effect on carbachol or electrical field stimulation induced contractions of isolated bladder strips, whereas other drugs used for abnormally frequent micturition inhibited both contractions. These results suggest that TAK-637 inhibits the micturition reflex by acting, at least in part, on NK1 receptors in the spinal cord, a mechanism of action clearly different from antimuscarinics or spasmolytics
NK-1 receptor antagonists, and in particular, those whose use is claimed herein, are also believed to be useful in the treatment of Lower Urinary Tract Symptoms (LUTS).
See Moller, et. al., BMJ 2000; 320: 1429-1432 (27 May); Pinnock and Marshall, MJA 1997; 167: 72-75 (21 July); Moller, et. al., Obstetrics & Gynecology 2000; 96:446-451; and Clinical Practice Guidelines: The Management of Uncomplicated Lower Urinary Tract Symptoms in Men, UHMRC 2000.